Thesis
The development of novel combinations therapies for the treatment of triple negative breast cancer
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T16867
- Person Identifier (Local)
- 201983695
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Introduction: Cancer has one of the highest mortality rates in humans, second only to heart disease. In 2018 there was an estimated 9.6 million deaths due to cancer. Cancer survival rates vary according to malignancy type, however modern medicine has improved cancer survival rates globally. Despite recent advancements, certain hard to treat cancers such as brain, pancreatic and triple negative breast cancer still have a poor prognosis. Therapy resistance is one of the major contributing factors to the failure of cancer therapy, leading to relapse, metastasis, and mortality. Radio- and chemoresistance can occur for a variety of reasons. One of the major contributing factors to therapy resistance is tumour heterogeneity, related to epigenetics, genomic instability, and therapy related mutagenesis. Thus, during treatment, cancer cells continue to evolve and mutate often to therapy resistant phenotypes. Over the course of the disease and its treatment, cancers therefore become more heterogeneous and are composed of pockets of tumour cells which are molecularly distinct from others and possess differential levels of sensitivity to therapies. As a result of this, many current cancer therapies have limited success and more optimal combination chemoradiotherapies are therefore required. Materials and methods; Triple negative breast cancer cells were cultured in 2D and 3D models to investigate the efficacy of combination therapies designed from eitherchemotherapy or irradiation and a pre-approved fumaric acids dimethyl fumarate and monomethyl fumarate. Dimethyl fumarate and monomethyl fumarate have been shown to inhibit the NRF2 activation via the DJ-1 stabiliser which induces oxidative stress and promoted cancer cell death, dimethyl fumarate is currently used as a treatment for several autoimmune diseases. Triple negative breast cancer cells resistant to Radiation and Chemotherapy were developed in house by serial culture and used to investigate novel combination therapies to overcome resistance. Clonogenic Assays and Spheroid analysis was used to investigate toxicity and mechanistic studies such as Comet Assay, Cell Cycle analysis, Annexin V, Glutathione Assay and Autophagy Assay were carried out to understand the mechanisms underpinning observed effects. The chick embryo model, a promising method of in vivo analysis was also investigated for its potential as a model to be used in the development of novel therapies. Results and Discussion; Specifically scheduled combination therapies using Chemotherapy and Radiation with monomethyl fumarate in toxicity studies, showed a statistically significantly reduction in cell survival when compared with the control and the individual treatments alone. Mechanistic studies suggest an increase in DNA damage, depletion in glutathione levels and cell cycle arrest between combination therapy, control, and single treatments. These findings in triple negative breast cancer cells were mirrored in the resistant cells, providing a possible combination therapy that can be used to overcome resistance in triple negative breast cancer patients. Conclusion: Our research focuses on utilising medicines already approved for other conditions and using them in combination with current therapies to improve the efficacy of the treatment and potentially reduce the amount of chemotherapy/radiotherapy required. The results found provide a promising potential treatment option for TNBC patients with recurring cancer. In addition, it was determined that the chick embryo model could be used as an in vivo model to investigate novel therapies to treat cancer.
- Advisor / supervisor
- Boyd, Marie
- Resource Type
- DOI
- Date Created
- 2023
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PDF of thesis T16867 | 2024-04-10 | Public | Télécharger |